Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6](Cl)[C:5]=1[N+:18]([O-:20])=[O:19].[NH3:22].C(O)C.C(=O)=O.CC(C)=O>O>[CH3:1][N:2]([NH:3][C:4]1[C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH2:22])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:21]
Reactant: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: N
Agent: O=C=O
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(N)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A 50 ml. Pyrex ampule was charged with N-dimethylamino-3-chloro-2,6-dinitro-4-trifluoromethylaniline (5.0 g.; 0.015 mole), ethanolic ammonia (8.54 g. of 6.06% w/w solution; 0.03 mole) and enough absolute ethanol to bring the liquid level to within one inch of the neck. The ampule was chilled in a bath of dry ice-acetone, sealed, heated with hot water (65°-75° C.) until the starting material was in solution, and then placed in an oven at 65° C. After heating at 65° C. for 72 hours, the ampule was opened and the reaction mixture was transferred to a flask and evaporated to dryness under vacuum. Cyclohexane (200 ml.) was added to the residue. The resultant mixture was heated under reflux for one hour, then filtered hot and allowed to cool to 40° C., at which temperature the product began to crystallize. The solution was decanted away from a small amount of solids and the product was allowed to crystallize slowly from the decantate by standing at room temperature overnight. The crystalline product was collected by filtration to obtain 2.7 g., m.p. 150°-153.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>C(#N)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Cl
Product: Clc1cc(N2CCNCC2)ncn1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
A solution of 14.8 g of 4,6-dichloropyrimidine in 100 ml of acetonitrile is cooled to 0-5° C., a solution of 20 g of anhydrous piperazine in 200 ml of acetonitrile is added over 30 minutes and the mixture is left with stirring at 0-5° C. for 2 hours. It is concentrated under vacuum, the residue is taken up with 100 ml of 2N NaOH and extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The hydrochloride is formed, giving 15 g of the expected product.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(CCc2ccccc2)cc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccc(CCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5.08 g (9.81 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{[p-(2-phenylethyl)phenyl]methyl}hexanoic acid in 22 ml of DMF are silylated, under a protective gas, with 6.80 g (45.1 mmol) of tert-butyldimethylchlorosilane and 5.48 g (80.4 mmol) of imidazole at RT for 20 h. The reaction mixture is poured onto 500 ml of ice-water, and this mixture is extracted 3× with ethyl acetate. The organic phases are washed with 10% citric acid solution, 2× water and saline, dried with Na2SO4 and evaporated. The residue is dissolved in 119 ml of methanol and 46 ml of THF, and this solution is treated with 8.1 g of potassium carbonate and 46 ml of water, and then stirred at RT for 17 h. The reaction mixture is subsequently poured onto ice-cold 10% citric acid solution, and this mixture is extracted 3× with ethyl acetate. The organic phases are washed with 2 portions of water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate 2:1→1:1→ethyl acetate) results in the pure title compound: TLC Rf (D)=0.22; tRet (II)=23.3 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(Sc2ccc3ccccc3c2)cc1
Yield: 0 %

Procedure:
2-(4-nitrophenylthio)naphthalene (9.2 moles, 2.6 g) was dissolved in 50 ml ethanol and 20 ml ethyl acetate and hydrogenated for 16 hrs at room temperature over 1.0 g 5% Pd/C. The solution was filtered through celite and concentrated to yield 2-(4-aminophenylthio)naphthalene 1.1 g, 47%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[F:13][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.CO.O=P(Cl)(Cl)Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[F:13]
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: CC#N
Product: O=c1[nH]cc(F)c2cc(Br)ccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 6-bromo-2h-isoquinolin-1-one (5.0 g, 22.32 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) (9.49 g, 26.8 mmol, Air Products, Allentown, Pa.). Methanol (55.8 ml) and acetonitrile (55.8 ml) were added and the reaction was heated to 50° C. and stirred for one hour. The reaction was concentrated, dissolved in DCE (110 mL), and POCl3 (4.16 ml, 44.6 mmol) was added. The reaction was stirred at 50° C. for one hour. The reaction was quenched into ice water and extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford crude 6-bromo-4-fluoroisoquinolin-1(2H)-one as a light pink solid. (ESI) 242.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C@@H:13]2[C@H:8]([C:9]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20].Cl>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[CH2:1]([N:4]1[C@@H:13]2[C@H:8]([C:9]3[CH:17]=[CH:16][C:15]([NH:18][S:28]([C:25]4[CH:26]=[CH:27][C:22]([CH:19]([CH3:21])[CH3:20])=[CH:23][CH:24]=4)(=[O:30])=[O:29])=[CH:14][C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCC[C@H]2c3ccc(N)cc3CC[C@@H]21
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCN1CCC[C@H]2c3ccc(NS(=O)(=O)c4ccc(C(C)C)cc4)cc3CC[C@@H]21
Temperature: 5 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
(4aS,10bS)-4-Allyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-8-ylamine (60 mg, 0.23 mmol) was dissolved in pyridine-dichloromethane (1:2, 7.5 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (50 mg, 0.24 mmol) was added and the solution stirred at 5° C. for 3 h. Solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated and separated by column chromatography (dichloromethane-3% MeOH) to give an oil. The oil was dissolved in ethyl acetate and HCl (4M, dioxane) was added to give the product as a white solid (20 mg, 15%).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([OH:11])[CH3:10].[C:12](O)(=O)[CH3:13]>>[OH:11][C:9]1[CH:3]=[CH:2][C:1]([C:12]2[NH:7][C:1]3[C:6]([CH:13]=2)=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:6][CH:10]=1
Reactant: CCO
Reactant: NNc1ccccc1
Reactant: CC(=O)O
Product: Oc1ccc(-c2cc3ccccc3[nH]2)cc1

Procedure:
A mixture of 40.8 g (0.3 mol) of 4-hydroxy-acetophenone, 33 ml (0.3 mol) of phenylhydrazine, 100 ml of ethanol and 1.5 ml of acetic acid was refluxed under nitrogen for 10 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1)([O-])=O.[C:17]1(=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>CC1C=CC(C(C)C)=CC=1>[C:2]1([NH:1][C:25]2[C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][CH:24]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCc2ccccc21
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 185 °C

Procedure:
To a 200 ml, 3-necked round bottom flask equipped with a thermometer and a Dean-Stark apparatus filled with p-cymene and having a condenser are added 7.45 g (80 mmole) of aniline, 4.82 g (39 mmole) of nitrobenzene, 14.6 g (100 mmole) of 1-tetralone and 65 ml of p-cymene solvent. Also introduced were catalyst and various acid promoters as indicated in Table I. The reaction mixtures were heated at reflux (about 185° C.) for 5 hours while removing the evolving water. Thereafter, the mixture was cooled to room temperature, and the catalyst was filtered out using a Celite (trademark) diatomaceous earth filter. The reaction mixture was analyzed by gas-liquid phase chromatography (GLPC) against a PANA standard. The yields mentioned in Table I are based on conversion of tetralone to PANA.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.CO[C:22](OC)([CH3:24])[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][C:22]1([CH3:24])[O:17][CH2:16][C:13]2([CH2:12][CH2:11][CH:10]([CH2:9][OH:8])[CH2:15][CH2:14]2)[CH2:18][O:19]1
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)(CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OCC2(CCC(CO)CC2)CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 391D (1 g) and 2,2-dimethoxypropane (1.276 mL) in N,N-dimethylformamide (6.93 mL) was added para-toluenesulfonic acid monohydrate (1.451 g). The reaction was stirred for 4 hours at room temperature, triethylamine was added and the solution was concentrated by rotary evaporation. The residue was placed under high vacuum overnight to remove N,N-dimethylformamide. The residue was purified by regular phase flash column chromatography (Analogix—0-100% hexanes/ethyl acetate).
Reaction SMILES: C(O[CH2:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:11]([OH:13])=[O:12])C1C=CC=CC=1.CC[OH:21]>[Pd]>[OH:21][CH:16]([CH2:17][CH3:18])[CH2:15][CH2:14][C@@H:10]([CH3:9])[C:11]([OH:13])=[O:12]
Reactant: CCO
Reactant: CCCCC[C@H](COCc1ccccc1)C(=O)O
Agent: [Pd]
Product: CCC(O)CC[C@@H](C)C(=O)O
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (R)-3-benzyloxy-2-pentyl-propionic acid (1.54 g, 6.16 mmol) in EtOH (100 mL) was added 10% Pd/C (310 mg). The reaction mixture was subjected to hydrogenation overnight at room temperature. After the reaction was completed, the reaction mixture was filtered through a pad of Celite, and washed with EtOH (50 mL×3). Removal of the solvent provided the title compound (0.92 g, 93%). No further purification was required. 1H NMR (400 MHz, CHCl3) δ 6.30 (br s, 1H), 3.81 (d, J=5.4 Hz, 2H), 2.64 (m, 1H), 1.69 (m, 1H), 1.56 (m, 1H), 1.41-1.27 (m, 6H), 0.91 (t, J=7.7 Hz, 3H). MH+161.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:33])[C:12]2[C:7](=[C:8](OC(=O)CCCC)[CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.C[OH:43]>[OH-].[Na+]>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:33])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:43])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Oc1cccc2c(=O)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c(CCCC)nc12
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc2ccc(O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 2-butyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-8-valeryloxy-4(3H)-quinazolinone (0.3 g) in methanol (5 ml) and 1N sodium hydroxide (2 ml) was stirred at room temperature for 1 hour. After addition of 1N hydrochloric acid, the reaction solution was extracted with ethyl acetate and the organic layer was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give a crystalline product. Recrystallization from ethyl acetate-ether gave colorless crystals (0.2 g, 80%), mp 212°-214° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12]([O:13][C:14]2[C:15]([C:27]#[N:28])=[N:16][CH:17]=[C:18]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:19]=2)=[C:11]([CH3:29])[CH:10]=[CH:9][N:8]=1.[OH-:30].[Na+]>>[CH3:6][C:7]1[C:12]([O:13][C:14]2[C:15]([C:27]([NH2:28])=[O:30])=[N:16][CH:17]=[C:18]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:19]=2)=[C:11]([CH3:29])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Concentrated sulfuric acid (8 mL) was added to 3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (2.03 g, 6.07 mmol). The reaction was stirred overnight, then poured onto ice (100 g), cooled in an ice batch and made basic to pH 10 with 50% NaOH. The reaction was extracted with ethyl acetate, washed with brine, dried (MgSO4), and concentrated to afford 3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinoamide (2.02 g, 5.73 mmol, 94.4% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH:7]([CH2:9]O)[C:6]([NH:16][C:17]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[S:18])([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH2:5]1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([N:4]1[CH2:8][CH:7]2[C:6]([C:11]3[S:15][CH:14]=[N:13][CH:12]=3)([N:16]=[C:17]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:18][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2cncs2)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCN1CC2CSC(NC(=O)c3ccccc3)=NC2(c2cncs2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
To a solution of N-[[1-allyl-4-(hydroxymethyl)-3-thiazol-5-yl-pyrrolidin-3-yl]carbamothioyl]benzamide (60 mg, 150 μmoles) in tetrahydrofuran (1 mL) at 0° C. is added triphenylphosphine (80 mg, 30 μmoles) and di-t-butyl azodicarboxylate (88 mg, 30 μmoles). The mixture is stirred for 30 minutes at 0° C., warmed to room temperature and stirred for 1 hour. The mixture is concentrated and purified over silica gel eluting with methanol/dichloromethane (0-5%) to give the title product (26 mg, 70 p moles, 45%). ES/MS (m/e): 385 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31].C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[O:31])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: O=C(O)c1ccccn1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(N)c2cc(C(=O)Nc3ccc(CNC(=O)c4ccccn4)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of 27 mg (0.05 mmol) 4-amino-N-[4-(aminomethyl)phenyl]-2-methyl-6-quinolinecarboxamide, 7 mg (0.1 mmol) 2-pyridinecarboxylic acid, and 0.028 ml (0.2 mmol) triethylamine in 2 ml DMF was added 36 mg (0.75 mmol) PyBrop and stirred at room temperature for 1 d. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 7.4 mg (23%) of the title compound. MS 412.3 (M+1)+, 1H-NMR (DMSO-d6) δ 2.60 (s, 3H), 4.47 (d, 2H), 6.64 (s, 1H), 7.33 (d, 2H), 7.60 (m, 1H), 7.70 (d, 2H), 7.86 (d, 1H), 8.00 (t, 1H), 8.04 (t, 1H), 8.35 (d, 1H), 8.65 (m, 1H), 8.94 (s, 1H), 8.98 (br. 2H), 9.32 (t, 1H).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]1[CH:7]=[CH:6][S:5][N:4]=1.C([Li])CCC.[CH2:14]([Sn:18]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])Cl)[CH2:15][CH2:16][CH3:17].C([O-])(O)=O.[Na+]>C1COCC1>[F:1][CH:2]([F:8])[C:3]1[CH:7]=[C:6]([Sn:18]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:15][CH2:16][CH3:17])[S:5][N:4]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: FC(F)c1ccsn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)F)ns1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 3-(difluoromethyl)isothiazole (93 mg, 0.688 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.473 mL, 0.757 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (0.223 mL, 0.826 mmol) in anhydrous THF (0.5 mL) was added and the reaction mixture was stirred for 30 minutes at −78° C. The solution was subsequently allowed to warm to room temperature over a period of about one hour. Saturated aq NaHCO3 was added, and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, passed through a short pad of silica gel (eluting with EtOAc) and evaporated in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:17][N:18]=[C:19]=[S:20].C(Cl)(Cl)Cl.CO.N>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:19]([NH:18][CH3:17])=[S:20])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN=C=S
Reactant: N=C(N)Nc1nc(C2CCCC(N)C2)cs1
Agent: N
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CNC(=S)NC1CCCC(c2csc(NC(=N)N)n2)C1

Procedure:
To a solution of 2-guanidino-4-(3-aminocyclohexyl)thiazole (0.6 g.) in ethanol (20 ml) was added methylisothiocyanate (0.18 g.) and the resulting solution was heated under reflux for two hours. The residue obtained on evaporation of the ethanol was subjected to column chromatography on silica gel (Kiesilgel 60, Merck) using chloroform/methanol/ammonia (s.g. 0.88) 8:2:0.3 v/v/v for development. The product, 2-guanidino-4-[3-(3-methylthioureido)cyclohexyl]thiazole, (0.4 g.) was obtained as a glass. The n.m.r. spectrum, in d6 dimethylsulphoxide, included resonances at 1.2-2.2(m,9H);2.8(d,3H); 4.0(m,1H); 6.2(s,1H); 6.8(br s,4H); and 7.2(br d,2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.[CH:10]([CH:12]=[CH2:13])=[O:11]>O1CCOCC1>[N:1]1[CH:5]=[CH:4][N:3]2[CH2:13][CH2:12][CH:10]([OH:11])[C:2]=12
Reactant: C=CC=O
Reactant: c1c[nH]cn1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: OC1CCn2ccnc21

Procedure:
To a solution of imidazole (2 mL, 30.26 mmol) and acetic acid (0.12 mL, 2.12 mmol) in dry dioxane (20 mL) under N2 was added acrolein (3.03 mL, 45.39 mmol) in 1 portion and the resultant solution heated to reflux for 4 hr. The reaction mixture was concentrated in vacuo and the yellow-brown residue was purified by column chromatography, (elution with 25% methanol in DCM) to give the title product; 1H NMR (500 MHz, DMSO) delta 2.25 (1H, ddt, J=13.06, 7.90, 3.94, 3.94 Hz), 2.70-2.87 (1H, m), 3.85 (1H, ddd, J=10.72, 8.51, 4.26 Hz), 4.03 (1H, ddd, J=10.72, 7.80, 6.23 Hz), 4.86 (1H, dd, J=7.09, 3.00 Hz), 5.58 (1H, br. s.), 6.94 (1H, s), 7.06 (1H, d, J=0.95 Hz); LC-MS: m/z=+124.9 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl.[CH2:16]([O:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC(F)(F)C(O)=O>N1C=CC=CC=1.C(Cl)Cl>[CH2:16]([O:23][N:24]=[C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CON=C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-oxopiperidine-1-carboxylate (524 mg, 2.63 mmol) and O-benzylhydroxylamine hydrochloride (504 mg, 3.16 mmol) in pyridine (5 mL) was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ether and H2O. The separated organic phase was washed with 1 N aqueous HCl and brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 816 mg of crude N-tert-butoxycarbonyl intermediate. This material was taken up in CH2Cl2 (5 mL), followed by addition of trifluoroacetic acid (5.0 mL, 65.0 mmol) via syringe. After stirring for 30 minutes at ambient temperature, the reaction was cooled to 0° C. and quenched by slow addition of 2 N aqueous NaOH solution (35 mL). The mixture was diluted with 75 mL CH2Cl2 and the phases were separated. The organic layer was washed with 1 N aqueous NaOH solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.27 (m, 5H), 5.07 (s, 2H), 3.02-2.94 (m, 2H), 2.94-2.86 (m, 2H), 2.63-2.54 (m, 2H), 2.33-2.23 (m, 2H), 1.58 (bs, 1H); MS (DCI+) m/z 205 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][OH:5])[CH3:3].[C:6]([O:10][C:11](=[O:14])[CH:12]=[CH2:13])([CH3:9])([CH3:8])[CH3:7].[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:6]([O:10][C:11](=[O:14])[CH2:12][CH2:13][N:1]([C:23]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24])[C@H:2]([CH3:3])[CH2:4][OH:5])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C[C@@H](N)CO
Reactant: C=CC(=O)OC(C)(C)C
Product: C[C@H](CO)N(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
In analogy to the procedure described in intermediate 8A, D-alaninol, tert-butyl-acrylate and N-(benzyloxycarbonyloxy)succinimide gave the title compound in quantitative yield as a light yellow oil. MS: 338.1 (MH+).
Reaction SMILES: [Br:1]Br.[C:3]1([CH:9]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C>[BrH:1].[Br:1][C:17]1[S:16][C:15]2[CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][NH:11][CH2:12][CH2:13][C:14]=2[CH:18]=1
Reactant: c1ccc(C2CNCCc3ccsc32)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Brc1cc2c(s1)C(c1ccccc1)CNCC2

Procedure:
A solution of bromine in acetic acid (1.03 ml, 10% v/v solution) was added dropwise to a stirred solution of 8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (0.53 g, 2 mmol, hydrochloride salt converted to free base by extraction between dichloromethane and aqueous ammonia) in acetic acid (5 ml) at room temperature. After 30 minutes the mixture was evaporated and the blue coloured solid residue recrystallised from ethanol (10 ml) to give 2-bromo-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine hydrobromide (m.p. 197°).